Abstract
BackgroundPhosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC.MethodsCorrelation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan–Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism.ResultsCorrelation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo.ConclusionsDownregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.
Highlights
Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism
PGM1 expression is negatively correlated with survival outcome of gastric cancer (GC) patients and overexpressed in GC To investigate the role of PGM1 in GC, we analyzed the correlation between PGM1 expression and the survival time of GC patients based on the Kaplan–Meier plotter database
We found that patients with GC at stage III (Fig. 1a, b), simultaneously with higher expression of PGM1, had significantly shorter overall survival (OS) and progression-free survival (PFS)
Summary
The role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. The latest investigation of global cancer statistics showed that there were over 10,00,000 new cases of GC and that GC caused an estimated 7,69,000 deaths in 2020. It ranks fifth in incidence and fourth in mortality worldwide [1]. In recent years, targeted drugs have attracted much attention and significantly improved therapeutic regimens. The subpopulation who can potentially harvest benefits from targeted drugs is limited and the associated medical costs are relatively high. It is eagerly required to develop drugs that can be widely applied and simultaneously have high efficacy
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